Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in the United States and two of the greatest risk factors for CVD are male sex and age. In the past, the increased prevalence of CVD in men was thought to be due to the much higher levels of serum testosterone (T) in men than in women. However, recent studies have noted that low T, rather than high T, is associated with cardiovascular (CV) risk factors and CVD in men. In contrast, prospective studies examining the association between T and CVD are conflicting. In general, the negative prospective studies included younger men with higher T levels and lower event rates. Given the conflicting results of prospective studies, the question remains whether low T is a risk factor for incident CV-events in older men who are at greater risk for CVD than middle-aged men. The primary goals of our study are to examine if low T levels are a significant risk factor for incident CV-events in older men and whether subclinical CVD and inflammation modify these relationships. Our specific aims are to examine if: 1) Low T predicts incident CV-events (myocardial infarction (MI), heart failure (HF), stroke, CV-mortality) and total mortality. 2) Low T is associated with subclinical CVD and if subclinical CVD modifies the association between low T and incident CV-events. 3) The inflammatory markers, (CRP, fibrinogen, WBC) modify the association between low T and incident CV-events. We will measure T levels in stored sera collected in 1994 from men, age >65 years, in the Cardiovascular Health Study (CHS) who had no history of CVD. As a primary aim, we will determine the relationship between T levels and time to incident CV-events, examined as a composite measure and separately by specific events (MI, HF, stroke, CV-mortality) and total mortality using Cox-regression models while controlling for relevant CV-risk factors. In preliminary CHS data, we found that men with low T levels had increased risk for incident HF, stroke, and total mortality. Based on these findings, we hypothesize that low T levels may be a novel risk factor for incident CV-events and mortality in elderly men. Our application is unique because it will be the first prospective study to examine the effects of low T levels on incident CV-events in a large population of elderly men with a long follow-up period, detailed clinical data, and high event rates. These factors will enable us to overcome the limitations of prior studies and rigorously examine our hypothesis that low T may be a novel risk factor for CVD in elderly men. PUBLIC HEALTH RELEVANCE: Our application will address whether low testosterone is a risk factor for incident cardiovascular events and mortality in elderly men and whether this association is modified by subclinical cardiovascular disease or inflammation. Given the growing number of elderly men with low testosterone, who are at high risk for cardiovascular disease, this is an important clinical question with potential substantive public health impact.